This invention is in the field of surgery, and more particularly, surgery to repair cartilage in joints such as knees, shoulders, or hips. It relates to the use of xe2x80x9cscaffoldxe2x80x9d devices that can be implanted in a joint with damaged cartilage, to help support certain types of transplanted cells (such as xe2x80x9cchondrocytexe2x80x9d cells) which can generate new cartilage. As used herein, the phrase xe2x80x9cdamaged cartilagexe2x80x9d is used broadly, and includes cartilage which has been damaged by mechanical trauma or other physical or inflicted injury or abrasion, or by a disease process, such as arthritis or osteoarthritis.
Background information on knee, hip, and shoulder joints, on cartilage tissue, and on xe2x80x9cclassicalxe2x80x9d techniques and devices that have been used for many years to repair damaged cartilage in knee joints are discussed in numerous medical texts, such as Campbell""s Operative Orthopedics, a five-volume treatise. Additional information is periodically issued by the American Academy of Orthopedic Surgeons in a series of books called xe2x80x9cOrthopedic Knowledge Updatesxe2x80x9d; volume 6 in that series was issued in 1999.
A number of recent articles and patents describe efforts to use transplanted chondrocyte cells, and various types of xe2x80x9cprecursorxe2x80x9d and xe2x80x9cstemxe2x80x9d cells, to generate new cartilage. Such articles include Brittberg et al 1994, Chen et al 1997, Minas et al 1997, and Thornhill 1997 (complete citations are provided below).
Most of the patents in this field tend to concur that the best way to promote cartilage regeneration inside a joint involves the use of a xe2x80x9cresorbablexe2x80x9d matrix, made of a material such as collagen, the protein that normally holds together connective tissue and provides the three-dimensional matrix that tissue cells grow in. In any type of connective tissue, the existing collagen fibers are slowly and gradually digested, mainly by an enzyme called collagenase. This process of gradual digestion of the old collagen is matched by a gradual secretion of new collagen fibers by the cells in the tissue, resulting in a process of turnover and replacement that helps keep tissue flexible, healthy, and strong. Accordingly, collagen implants (usually made from cowhide, which offers an abundant source of the fibrous protein, treated with cross-linking and other chemical agents to control the rate of enzymatic degradation) were developed for other purposes beginning in the mid-1970""s (e.g., U.S. Pat. No. 4,060,081, Yannas et al 1977).
Clearly, implantation of chondrocyte or similar cartilage-secreting cells in a damaged cartilage surface in a joint is a difficult and challenging task, which requires the cells to be anchored in position and then protected and sheltered from compressive and shear forces for a period of weeks or months, to give the transplanted cells a chance to generate firm and anchored cartilage without simply being squashed out of the joint. Accordingly, researchers began to realize by about the mid-1980""s that resorbable collagen matrices could be used to help position, protect, and anchor such cells in cartilage repair operations, and if properly designed, the matrix would gradually disappear once it had accomplished its task, leaving behind regenerated cartilage.
Accordingly, a large number of US patents were issued which centered around this theme, and which proposed various ways to enhance and improve the ability of the xe2x80x9cresorbable collagen matrixxe2x80x9d approach to repairing damaged cartilage. For example, U.S. Pat. No. 4,846,835 (Grande 1989) discloses techniques for giving chondrocyte cells (preferably taken from the same patient who has suffered the joint damage, so that no risk of rejection will be present) a headstart, by growing them outside the body in an in vitro cell culture solution, seeded and embedded into a collagen matrix. After the cells have been growing inside the collagen matrix for a suitable number of days, under lab conditions, the entire matrix (including the cells) can be surgically implanted into the damaged joint.
U.S. Pat. No. 4,880,429 (Stone 1989), U.S. Pat. No. 5,007,934 (Stone et al 1991), and U.S. Pat. No. 5,306,311 (Stone et al 1994) also relate to porous matrices made of collagen or similar compounds, which can be shaped or sculpted in various desired shapes, then implanted or xe2x80x9cseededxe2x80x9d, under laboratory conditions, with cells that reproduce to form large numbers of chondrocyte cells (which generate cartilage) or meniscal fibrochondrocytes (which generate meniscal tissue);
U.S. Pat. No. 5,041,138 (Vacanti et al 1991) describes a similar type of cell growth, in a biodegradable matrix made of a synthetic polymer rather collagen.
U.S. Pat. No. 5,206,023 (Hunziker 1993) relates to a multi-step process for repairing damaged cartilage, involving (i) enzymatic treatment to remove proteoglycans from the defect area, followed by (ii) packing the cleaned area with a degradable matrix that encourages ingrowth of repair cells.
U.S. Pat. No. 5,518,680 (Cima et al 1996) discloses the use of various xe2x80x9csolid free-formxe2x80x9d manufacturing techniques which can be aided by xe2x80x9ccomputer-assisted designxe2x80x9d (CAD techniques, such as stereo-lithography, selective laser sintering, fusion deposition modeling, and three-dimensional printing, to rapidly manufacture colagen or other resorbable matrices in precise dimensions that are determined based on the dimensions of the defect in a particular patient. The ""680 patent also discloses the incorporation of certain inorganic particles in such matrices, both to strengthen the highly porous matrices, and to provide a source of minerals for regenerating tissue.
U.S. Pat. Nos. 5,749,874 and 5,769,899 (both Schwartz et al 1998) disclose a two-component implant, where one component is a holding and anchoring device, made of a relatively hard yet biodegradable material such as polyglycolic acid, polylactic acid, or combinations therof. This anchoring device is designed to to hold a more porous and flexible matrix, made of a material such as collagen or hyaluronic acid, which will hold chondrocyte cells.
Various other patents focus on alternatives to collagen, in biodegradable matrices. Such patents include U.S. Pat. No. 5,294,446 (Schlameus et al 1994), which discloses that alginate (a naturally occurring polysaccharide) can be used to encapsulate of live cells. U.S. Pat. No. 5,041,138 (Vacanti et al 1991), U.S. Pat. No. 5,709,854 (Griffith-Cima et al, 1998) and U.S. Pat. No. 5,736,372 (Vacanti et al 1998) provide extensive information on various synthetic polymers (such as polyphosphazines, polyacrylates, polyanhydrides, and polyorthoesters, as well as xe2x80x9cblock copolymersxe2x80x9d such as mixtures of polyethylene oxide and polypropylene glycol) which can be used to generate hydrogels which can used for cartilage replacement.
These listed patents also contain citations to numerous published articles that are directly relevant in this field. Alternately, an Internet search of the National Library of Medicine database, available for free at http://www.igm.nih.gov, combining xe2x80x9ccartilagexe2x80x9d as a subject or title word combined with xe2x80x9cLangerxe2x80x9d or xe2x80x9cVacantixe2x80x9d as an author name, will quickly provide a generous supply of information on the current state of the art in this field.
It should be noted that some of the polymers listed in the Vacanti et al patents cited above were chosen and developed to repair facial cartilage (mainly in the nose and ears) rather than for repairing load-bearing cartilage in joints. In general, cartilage in the nose and ears is softer and more flexible than xe2x80x9chyalinexe2x80x9d or xe2x80x9carticulatingxe2x80x9d cartilage which occurs in knees, hips, and other joints. Accordingly, although the ""854 and ""372 patents disclose and discuss a long list of potentially suitable biocompatible synthetic polymers, all of which can support chondrocyte growth for a prolonged period and then eventually disappear due to resorption, any synthetic polymer intended for use in a knee, hip, or other load-bearing joint will need to be selected accordingly, with careful attention to its load-bearing traits.
Two quantifiable traits which are important are called dynamic stiffness, and aggregate modulus. Dynamic stiffness is discussed in articles such as Vunjak-Novakovic et al 1999, and is usually expressed in this field of art in terms of megaPascals (mPa). The dynamic stiffness of natural hyaline cartilage is usually about 10 mPa. Aggregate modulus is discussed in articles such as Ma et al 1995, and is usually expressed in terms of kiloPascals (kPa). The aggregate modulus of natural hyaline cartilage is usually about 450 kPa.
A number of patents in this field of art focus on the use of specialized molecules which can stimulate certain processes that are useful during cartilage regeneration. An early patent in this field was U.S. Pat. No. 4,609,551 (Caplan et al 1986), which claimed that xe2x80x9csoluble bone proteinsxe2x80x9d can induce certain types of cells to begin secreting cartilage. During the following decade, as various proteins were identified in greater detail, subsequent patents claimed that (i) certain xe2x80x9ctransforming factorsxe2x80x9d can be used to cause xe2x80x9cprecursorxe2x80x9d chondrocytes or other xe2x80x9cstemxe2x80x9d cells to mature into chondrocyte cells that actively secrete collagen (e.g., U.S. Pat. No. 5,206,023, Hunziker 1993); (ii) certain xe2x80x9cchemotacticxe2x80x9d agents can be used to encourage xe2x80x9crepair cellsxe2x80x9d to migrate into a cartilage defect being repaired (e.g., U.S. Pat. Nos. 5,206,023 and 5,270,300, both Hunziker 1993); and, (iii) certain xe2x80x9cmitogensxe2x80x9d, also called xe2x80x9cproliferation agentsxe2x80x9d, can be used to cause chondrocyte cells to reproduce more rapidly (e.g., U.S. Pat. No. 5,206,023, Hunziker 1993). Each of those categories of hormones and xe2x80x9cfactorsxe2x80x9d is indeed useful for stimulating and accelerating the cellular processes disclosed herein, and the invention specifically anticipates that each one of those categories of biologically active agents can be used in conjunction with the resorbable matrices disclosed herein.
Still other patents disclose other proposed devices and methods for using transplanted chondrocyte or other cells to replace and repair damaged cartilage. For example, U.S. Pat. No. 5,759,190 (Vibe-Hansen et al 1998) suggests that a xe2x80x9chemostatic barrierxe2x80x9d should be placed as a lining between a chondrocyte implant and the underlying cartilage, and that a protective xe2x80x9ccovering patchxe2x80x9d such as a cell-free collegen membrane should also be placed on top of the chondrocyte implant. U.S. Pat. No. 5,786,217 (Tubo et al 1998) discloses a method of growing a complete intact piece of cartilage outside the body, using in vitro methods and a pre-shaped growing well, and then surgically implanting the piece of cartilage into the defect, using sutures and/or adhesives to anchor it. U.S. Pat. No. 5,842,477 (Naughton et al, 1998) discloses the use of certain types of periosteal and/or perichondrial tissue in conjunction with chondrocyte implants, to promote the migration of chondrocyte, progenitor, or stromal cells into the area being repaired.
Despite all of the foregoing, the methods and devices disclosed in the articles and patents cited above suffer from various limitations. Perhaps the most important limitation arises from the fact that under the current state of the art, chondrocyte cell transplants can only be used to repair cartilage defects that are about 1 square centimeter, or smaller, in size. Diligent efforts to work with larger areas have been tried, but the success rates in such efforts decrease when the size of the cartilage defect increases, and by the time a defect that needs to be repaired covers about 2 square centimeters or more, the success rate is very low. Therefore, repair of a large defect in a cartilage surface of a knee normally requires a xe2x80x9ctotal knee replacement.xe2x80x9d Accordingly, although chondrocyte transplants are useful for treating many types of sports injuries and other types of mechanical trauma or injury (such as automobile or bicycling accidents, falls, etc.), they are severely limited, and in most cases totally useless, for treating elderly patients, patients suffering from osteoarthritis, and various other types of patients with defects larger than about 1 to about 1.5 square centimeters.
In addition to that size limitation, collagen or other porous proteinaceous matrices disclosed in the patents by Stone, Hunziker, or Grande are not tough and durable, so it is difficult or impossible to anchor them to a bone surface that is subject to loading conditions.
It also should be recognized that repair methods involving transplanted chondrocyte cells under the prior art require long recovery times, compared to other approaches such as a xe2x80x9ctotal knee replacementxe2x80x9d using a mechanical joint. Typically, a patient receiving a chondrocyte cell transplant in a knee joint is prohibited from putting any weight on the knee for at least 6 weeks, and many patients are told to not put any weight on the knee for even longer periods, such as 12 weeks. Even after a patient can begin using the knee again, full recovery from chondrocyte cell transplant surgery typically requires numerous months. This type of slow and prolonged recovery period greatly increases the total costs of treatment and recovery (including, in many cases, lost work and lost wages). By contrast, a patient who has a xe2x80x9ctotal knee replacementxe2x80x9d (TKR, which involves sawing off and removing a damaged knee joint and replacing the joint with a mechanical device attached to the tibia and femur bones by steel pins) can usually begin to put weight back on the knee within a day or two after the surgery.
The very long recovery period required by chondrocyte cell transplants under the prior art also tends to limit candidate patients to relatively young people who were injured in a sporting event, auto accident, etc. Elderly patients, who are not as active and who will not have to live with a serious knee problem for another 40 years or more, are usually advised to get xe2x80x9ctotal knee replacementxe2x80x9d surgery instead.
Accordingly, one object of this invention is to disclose improved methods and devices for using transplanted cells to help repair damaged cartilage in a joint, using scaffold devices to enlarge the area and volume that can be treated by the transplanted cells.
Another object of this invention is to disclose a resorbable scaffold device made of two different materials. One is a relatively stiff matrix material, to provide load-bearing support. The other matrix material is designed for maximal rapid generation of new cartilage, and can be substantially softer and more highly porous.
Another object of this invention is to disclose a method of enlarging the size of an area of damaged cartilage that can receive transplanted chondrocyte or other cells, by means of a resorbable scaffold that effectively subdivides the large area into a cluster of smaller areas, each of which is surrounded and protected by walls and xe2x80x9crunnersxe2x80x9d made of the relatively stiff matrix material.
Another object of this invention is to disclose a method of combining two different and distinct technologies (chondrocyte cell transplants, and flexible scaffold devices that can be inserted into a joint using arthroscopic tools and minimally-invasive incisions), to provide a hybrid form of treatment that offers improved methods of arthroscopic repair of damaged cartilage in joints such as knees.
These and other objects of the invention will become more apparent through the following summary, drawings, and description of the preferred embodiments.
A load-sharing resorbable scaffold is used to help transplanted chondrocytes or other cells generate new cartilage in a damaged joint such as a knee, hip, or shoulder. These improved scaffolds use two distinct types of porous matrix materials. One is a relatively stiff matrix material, which is designed to withstand and resist a compressive articulating load that is placed on the joint during the convalescent period shortly after surgery. Due to the mechanical requirement for a relatively high stiffness, this matrix material must be denser and have less pore space than other available matrices. Accordingly, it will not be able to support as much cell proliferation and cartilage secretion as other matrices which have higher levels of porosity. The second type of material comprises a more open and highly porous matrix material which is designed to promote maximal rapid generation of new cartilage. In one preferred geometric arrangement, the stiffer matrix material is used to provide an outer rim and one or more internal runners, all of which can distribute a compressive load between them. The rim and runners create a cluster of internal cell-growing compartments, which are filled with the more porous and open matrix material to encourage rapid cell reproduction and cartilage generation.
These improved scaffolds can also have an articulating outer membrane with certain characteristics disclosed herein, bonded to and resting upon the upper edges of the internal runners and outer rim. The scaffold will support the outer membrane with a degree of stiffness and resiliency that allows the membrane to mimic a healthy cartilage surface.
As a further option, these scaffolds can be made of flexible materials. This will allow them to be inserted into a damaged segment of cartilage using arthroscopic methods and tools, to minimize surgical damage to tissue and blood vessels in the vicinity of the joint.